Can resistance prehabilitation training bring additional benefits in valvular cardiac surgery? protocol for a randomized controlled trial

Introduction Cardiovascular diseases (CVD) are a group of illnesses that include coronary heart disease, cerebrovascular disease, congenital heart disease and deep vein thrombosis. Major surgery is often chosen as the treatment of choice for CVD. The concept of fast-track rehabilitation after surgery appeared in the 1970s. Participation in these exercise-based prehabilitation programmes may decrease postoperative complications and length of hospital stay. The primary aim of the present study is to evaluate whether the implementation of an additional resistance training (RT) prehabilitation protocol within cardiac exercises based prehabilitation can reduce intensive care unit (ICU) length of stay, postoperative complications and hospital length of stay (LOS). Methods A protocol of a prospective, parallel, randomised clinical trial includes 96 adult patients diagnosed with valvular pathology and who have been scheduled for surgery. The participants will be randomly assigned to two groups of 48. Control group will be treated with ventilatory and strengthening of respiratory muscles, and aerobic exercise. Experimental group, in addition, will be treated with RT of peripheral muscles. Both hospital stay and ICU stay will be assessed as main variables. Other secondary variables such as exercise capacity, quality of life and respiratory values will also be assessed. Quantitative variables will be analysed with a T-Test or ANOVA, or Mann Witney if the distribution is non-parametric. Results and conclusion This will be the first controlled clinical study focused on adding strength exercise as an additional treatment during prehabilitation. The results of this study will focus on helping to improve rehabilitation and prehabilitation protocols, considering that it is essential to maintain pulmonary training, as well as the inclusion of peripheral exercises that help people with heart disease to be in a better physical condition in order to increase their participation and sense of quality of life.


INTRODUCTION
Cardiovascular diseases (CVD) include coronary heart disease, cerebrovascular disease, congenital heart disease, deep vein thrombosis, pulmonary embolism, and disorders affecting the heart and blood vessels.(1).A number of risk factors are often associated with acute CVD (1,2) and, at the socio-demographic level, poorer economic or educational conditions may contribute to increased risk factors (3).CVD accounts for 31% of deaths and is the leading cause of mortality worldwide (1,4).(1,4).Coronary heart disease alone accounts for 19% of global deaths in men and 20% in women (1).(1).In Spain, according to the Instituto Nacional de Estadística, CVD caused 24% of all deaths in 2020 (5).
Major surgery is often chosen as the treatment of choice for CVD, with patients often classified as "high risk" due to comorbidities such as frailty, obesity or advanced age.(6).These patient characteristics may increase the likelihood of postoperative pulmonary complications such as pneumothorax, atelectasis, pneumonia, need for prolonged mechanical ventilation, pulmonary oedema or respiratory distress syndrome (7,8).
The concept of fast-track rehabilitation after surgery (ERAS, Enhanced recovery after surgery) appeared in the 1970s, and combines different measures to optimise the patient's condition before, during and after surgery in order to allow them to recover their maximum functional capacities as quickly as possible after the surgical procedure.(9)(10)(11)(12).Although this concept was initially introduced by surgeons, it is now a transdisciplinary approach that can only be successful with the synergistic involvement of the entire healthcare team.The ERAS (Enhanced Recovery After Surgery) protocol represents a model of patient-centred healthcare collaboration (9,11,13).Despite the name of the protocol, rehabilitation places great emphasis on both preoperative preparation and postoperative re-education (9)(10)(11)(12)(13).Furthermore, at a time when controlling health care costs is an ever-present concern, participation in these exercise-based prehabilitation programmes (EBPrehab) may decrease postoperative complications and length of hospital stay (LOS) (9,11,12).( 9) improving patients' functional capacity and decreasing healthcare costs (14).
An exercise programme that includes peripheral muscle strengthening, also known as resistance training (RT), has been shown to be effective in reducing in-hospital mortality and LOS in major abdominal surgery.(25,26).RT added to aerobic training can improve quality of life and left ventricular function in people with coronary heart disease (27).However, despite the wide variety of characteristics of cardiac prehabilitation programmes, to our knowledge, none of those published have included RT to study whether, as in other pathologies, there is a therapeutic advantage and a better evolution of patients operated on for valve disease, which would imply the development of a more efficient prehabilitation protocol.
Based on the above, the purpose of the present study is to evaluate whether the implementation of an additional RT prehabilitation protocol within a cardiac EBPrehab (based on aerobic training, ventilatory work and respiratory muscle strengthening) can reduce ICU length of stay, postoperative complications and LOS in valvular patients undergoing cardiac surgery.
In addition, the secondary objective is to find out whether a programme that includes RT in addition to respiratory and aerobic training can have better effects on ventilatory variables compared to a traditional programme based on aerobic exercise, ventilatory work and respiratory muscle strengthening.

Design
A prospective, parallel, non-randomised, single-centre, prospective clinical trial protocol has been designed.In this study, participants will be randomly assigned to either the experimental prehabilitation group or the conventional prehabilitation group during the three weeks prior to surgery.
This study complies with the ethical principles established in the Declaration of Helsinki and is made available to the Ethics Committee of the Hospital de La Ribera.If approved, it will be registered in the U.S. National Library of Medicine (ClinicalTrials.gov).All candidates will be given and explained an information sheet (Annex I) with detailed information on the study and will be asked for their express consent and signature, after reading and explanation, as a requirement for participation in the study.
Participants: eligibility and recruitment.
Ninety-six patients will participate in this study, whose recruitment is expected to take place between June 2023 and July 2025.The inclusion criteria for the sample will be: adult patients diagnosed with valvular pathology who have been admitted as candidates for cardiac surgery for the first time, and whose appointment for intervention has been scheduled.Only those who voluntarily agree to participate in the study and sign the informed consent form will be admitted.Patients with the following characteristics will be excluded: stage 4 or 5 renal failure, low ejection fraction, Euroscore greater than 15, non-ST-segment elevation acute coronary syndrome (NSTEACS) and coronary artery disease or need for urgent intervention.
Those with cognitive deficit, diagnosis of pulmonary disease, heart failure, unstable angina, arrhythmias, severe aortic stenosis, mitral regurgitation, aortic aneurysm, recent embolism, recent myocarditis or pericarditis, or comorbidities limiting the performance of the functional test will also be excluded.
All persons referred to the Physiotherapy Unit from the Cardiac Surgery Unit of the Hospital de La Ribera (Alzira, Spain) will be considered candidates for this study, as long as they attend the initial physiotherapy assessment.Recruitment will therefore be carried out among these attendees and eligibility will be confirmed by a physiotherapist.Signed informed consent will be collected prior to any measurement or intervention.
The assignment of each participant to one group or another is not the responsibility of the researchers, but will be randomised.The initial and final evaluation will be carried out by three physiotherapists who will act without knowing the assignment of each participant to one or the other group.The physiotherapists who carry out the measurements will attend a training session to unify the measurement criteria for each variable.

Intervention
Figure 1 shows how the intervention and measurement protocol will be developed in each of the groups.Both groups will receive a first session in which they will be instructed to carry out the unsupervised home EBPrehab programme, consisting of respiratory training, ventilatory work and strengthening of the respiratory muscles, aerobic endurance exercise through continuous walking, and a series of measures on post-surgical care.Once the guidelines have been explained, they will be given a series of links to explanatory videos so that they can carry out the work at home seven times a week without supervision.For this intensity adjustment, individual perception of exertion will be used, using a Borg CR-10 scale (29).Participants will be instructed to maintain a moderate intensity, between four and seven on this scale.Aerobic endurance exercises shall be performed in a continuous and harmonious rhythm.In addition, a preoperative musculoskeletal and cardiopulmonary rehabilitation programme will be implemented in the experimental group for the cardiovascular patient who underwent surgery for valvular heart disease.The intervention has been designed following the guidelines of the American College of Sports Medicine (ACSM) for exercise prescription, considering the FITT-VP principles (Frequency, Intensity, Type, Time, Volume, Progression) for patients with cardiorespiratory pathology and adjusting them to the surgical population.(28).This peripheral muscle strengthening programme (Figure 2) will be modified and adapted in each classroom session, which will require a weekly evaluation and modifications in terms of the load and the number of series and/or repetitions, depending on each participant (29).For this work, participants will also be educated to adjust the intensity using the Borg scale CR-10 (29)by asking them to maintain a moderate intensity, between four and seven on this scale.(Respironics, NJ 07054, USA), adjusting the workload to a minimum of 30% of the subject's PIM.(16,30).The workload range of the IMT device will be 9 to 41 cmH2O.The protocol will contain 20 min of training divided into seven sets, with two minutes of work and one minute of rest between sets.Each participant will receive a list of links to demonstration videos and instructions on how to perform each of the exercises.2. Aerobic endurance training phase (Conventional treatment group and experimental group), 10 min, increasing by five minutes at each training session, up to 20 min.Each patient will walk in a continuous harmonic mode, following the minimum recommendations of the World Health Organisation.(31).Perception of exertion will be assessed using a modified Borg scale.3. Peripheral resistance training phase (for the experimental group only).10 min, increasing by five minutes at each training session, up to 20 min.In each session, participants will complete three sets of four exercises.During the first sessions, training will consist of 8 repetitions of the exercises, performed with light resistance bands, and emphasising analytical training of the main muscles (deltoids, biceps brachii, triceps brachii, abdominals, trunk extensors, quadriceps, hamstrings and calves).(32).After the second training session in the hospital, progress to using medium resistance bands and/or increasing repetitions for each exercise.In the final phase, the volume will be increased to 12 repetitions.Each exercise will be rested for 60 seconds.
To verify that participants perform the exercises at home, regardless of the group to which they are assigned, they will be asked to record their activities at home using the Google Fit application.(33).
The prehabilitation programme common to all participants is the same programme that is conventionally carried out in the prehabilitation service of the Hospital La Ribera.In that sense, although there is no evidence that the exercises proposed before surgery can cause harm to cardiac patients awaiting surgery, to minimise the risks the first session will be carried out in the hospital, adapting the intensity to each individual.Any adverse situation perceived by the patient during the home sessions will be reported.All adverse effects will be evaluated, recorded and discussed in the final article.

Variables
The variables will be divided into four different areas, differentiating between hospital stay, quality of life, respiratory values and exercise capacity (Figure 3). 1. Hospital stay.Hospital stay will be measured in hours and minutes, so that stays of less than 24 hours can be better accounted for.Three different variables will be recorded:  Intensive Care Unit stay: counted from the end of the surgical procedure until transfer to the ward. Ward stay: counted from transfer to ward until discharge from hospital. Hospital stay: counted from the end of the surgical procedure until discharge from hospital.2. Quality of life.Perception of quality of life will be recorded and assessed both before and six months after surgery.The EuroQOL-5D quality of life questionnaire, valid and reliable for analysing quality of life in this type of patient, will be used.The participant assesses their capacity for self-care, mobility, activities of daily living, the presence of pain or anxiety/depression in categorical levels of severity (no problems, some problems or moderate problems and severe problems) and their perception of health using a visual analogue scale.(34).As there are no published data on the interexaminer reliability of this tool (35)a single nurse will be responsible for collecting these values.

Respiratory values. Respiratory values shall be collected on three different occasions:
before surgery, immediately after surgery and on the day of hospital discharge.These tests shall be repeated until three acceptable measurements are obtained (difference <10%), with a one-minute rest between them, and the highest value shall be recorded (36,37).Three measurements shall be made of:  Inspiratory capacity: This is defined as the volume of air that can be inspired from the resting inspiratory position.With the patient in a seated position, the Portex® Coach 2® 4000 ml incentive spirometer will be used to measure inspiratory capacity and the value of the variable will be expressed in millilitres.The patient will be instructed to take a deep, unforced inspiration, trying not to exceed the flow mark (38). Peak expiratory flow: This is defined as the maximum flow a person is able to exhale during a brief maximal expiratory effort after a full inspiration.With the patient in a seated position, the Sibelmed® Datospir Peak-10 device will be used to record the peak expiratory flow and the value of the variable will be expressed in litres/second.The patient will be instructed in a maximal forced expiration, preceded by a deep nasal inspiration up to inspiratory reserve volume (39). Respiratory pressures: These are used to calculate the strength of the respiratory muscles, both at the diaphragmatic (inspiratory) and abdominal and intercostal (expiratory) levels.Maximum static inspiratory pressures (MIP) and maximum static expiratory pressures (MEP) will be measured in a seated position, using a MicroRPM device (Carefusion, VYAIRE MEDICAL, UK).A careful explanation of the test will be given, encouraging the patient to perform a maximal inspiration and inspiration of approximately 2-3 seconds against the resisted device.Predicted values will be estimated using the equation proposed by Heinzmann et al.40).4. Exercise capacity.Exercise capacity and endurance will be collected before, 24 hours after surgery and at discharge.The tests used will be:  Aerobic capacity: will be assessed by the 2-minutes Step Test, a valid tool to assess functionality in patients with cardiac pathology after surgery and sensitive to assess perioperative changes.(41)which also has excellent interreliability (41).(41).Following the protocol established by Jones and (42)implemented in 2022 by Chow et al. in revascularised individuals (41)the aim of this test is to count the number of repetitions that each participant is able to perform in two minutes.In case a person needs technical assistance to perform the test, a stable chair will be placed close to him/her to limit the risk of falling.The assessor shall use a manual counter to record the number of steps each person takes by lifting one knee to the middle distance between the patella and the anterior superior iliac spine.(42). grip strength: grip strength capacity shall be recorded with manual dynamometry (kg), using a Jamar Plus+® device, which is reliable for measuring changes in patients with cardiac disease, and whose minimum detectable change is 5.2 kg and 5.1 kg for the right and left hand, respectively.(43).With the patient in a seated position, a maximum hand closure is requested for 2-3 seconds, the hand is changed, and the operation is repeated up to 3 times, with a difference of less than 10% between measurements.This tool has interexaminer reliability (44).
 Analytical strength of the biceps brachii and quadriceps femoris: The strength of the biceps brachii and quadriceps femoris will be measured on the arms and legs with a Dynamometer Lafayette Manual Muscle Tester (Lafayette, IN, USA).(45,46).The measurement technique was described by Bohannon, who verified the excellent intra-and inter-examiner reliability of this tool (47). Lower extremity strength: lower extremity strength will be assessed using the Short Physical Performance Battery, a functional test battery that is valid, reliable, sensitive to clinical functional changes and with adequate intraand inter-examiner reliability (48,49).(48,49).The test consists of three parts: o A five-squat test in standing position, reliable for measuring change, with a minimum detectable change of 3.12 seconds.(43).The time taken to perform the five squats will be categorised according to the following criteria: time less than or equal to 11.19

Statistical analysis.
An independent statistician will carry out the statistical analysis.He or she will have no knowledge of whether each participant belongs to one group or another, nor what type of treatment was implemented in each group.All necessary data will be extracted into an Excel spreadsheet and analysed using IBM® SPSS® Statistics 27.0.1.0.
A Kolmogorov-Smirnov test will be used to check whether or not the data fit a normal distribution.A descriptive analysis will be carried out to explore the variables related to the study.
Quantitative variables with parametric distribution will be assessed with a T-test or ANOVA, while if the distribution is non-parametric a Mann-Whitney test will be used.This analysis will examine whether there are differences between groups that may support or refute the hypothesis that strength training reduces hospital stay, ICU stay and/or complications in this type of patient.This analysis will also be used to test whether ventilation and respiration values as well as quality of life values are different in each group.
To assess whether there is an influence of confounding variables (BMI, toxic habits, comorbidities, underlying pathologies) on the direction of the dependent variables, multiple regression will be performed.

Sample size.
For the primary outcome (time in the intensive care unit), an effect size of 0.613 was determined based on previous research on the effect of a multidimensional preoperative intervention in patients awaiting elective coronary artery bypass graft surgery (47).To obtain a statistical power of 0.8 with a 2-tailed alpha of 0.05 in a Student's t-test, considering a dropout rate of 10%, a total of 96 participants (48 subjects per group) were required.

Data collection
Sex, age, underlying pathology, comorbidities, body mass index (BMI) and toxic habits will be the descriptive variables collected in both groups.All these data will be stored in their clinical history and will be extracted by the person in charge of epidemiological data management at the hospital, who will include them in an Excel table, also indicating whether each participant survives or not, as well as the information related to the intervention and the pathology, catalogued using the International Classification of Diseases 11 (ICD-11) or the appropriate one if there are updates.Days of hospitalisation, intensive care unit (ICU) stay, if applicable, Charlson comorbidity index, and possible postoperative complications for each participant will also be reflected in this table.
Although the database from which the data will be extracted will not contain personal data, as each participant will receive a numerical identification code, all researchers will sign a data confidentiality commitment sheet prior to the start of the study, which states that patients' personal data will be protected.
The medical information of each participant and his or her evolution at each point of the measurement shall be recorded in his or her medical record.

RESULTS
The results will first be expressed taking into account hospital and/or ICU stay as the primary variable.Also, to address secondary variables with criteria, values related to postoperative complications and quality of life will be cited.This will be followed by values related to functionality and muscular and aerobic endurance.Finally, it will be reflected whether confounding variables may interfere with the direction of dependent variables.
Quantitative variables will be expressed in terms of means and standard deviations, provided that they comply with a parametric distribution, or in medians and interquartile ranges if this is not the case.Box and whisker plots shall be used for their graphical representation.
Categorical variables, corresponding to the EuroQoL-5D items, will be expressed in terms of frequency and percentages and bar charts will be used for ordinal variables, while nominal descriptive variables will be expressed using pie charts.

DISCUSSION
In order to provide a better understanding of the most appropriate treatment for patients undergoing heart valve surgery, this will be the first controlled clinical study focused on adding strength exercise as an additional treatment during prehabilitation.This variable will be compared to a protocol focusing on strengthening respiratory muscles and improving ventilatory capabilities, which have already been shown to be effective in people undergoing major cardiac surgery (9,12,(15)(16)(17).To better understand the results, they will be carefully analysed, taking into account the special characteristics of the study sample.They will also be compared with the results reflected in other studies focusing on individuals with the same characteristics and focusing on similar objectives, albeit with other types of approaches.Therefore, future studies will be able to analyse our results and transfer the protocol to larger or different population groups.
The results of this study focus on helping to improve rehabilitation and prehabilitation protocols, considering that it is important to maintain pulmonary training, as well as the inclusion of peripheral exercises that help people with heart disease to be in better physical condition in order to increase their participation and sense of quality of life.
seconds; between 11.20 and 13.69 seconds; between 13.70 and 16.69 seconds; between 16.70 and 60 seconds; greater than 60 seconds or inability to perform.o Static balance, where the participant is asked to adopt three positions during standing: feet together, semi-tandem and tandem.It is quantified if the time they can hold the position is less than or at least 10 seconds.o Gait ability, where the patient will be asked to walk in a 4m corridor at a normal pace and the best time in seconds of two attempts will be recorded.Gait ability will be categorised as follows: Unable to perform, time greater than 8.7 seconds; time less than 8.7 seconds, but equal to or greater than 6.21 seconds; time less than 6.20 seconds, but greater than or equal to 4.82 seconds; time less than 4.82 seconds.